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@ARTICLE{Jocher:277534,
      author       = {Jocher, Georg and Ozcelik, Gozde and Müller, Stephan A and
                      Hsia, Hung-En and Lastra Osua, Miranda and Hofmann, Laura I
                      and Aßfalg, Marlene and Dinkel, Lina and Feng, Xiao and
                      Schlepckow, Kai and Willem, Michael and Haass, Christian and
                      Tahirovic, Sabina and Blobel, Carl P and Lichtenthaler,
                      Stefan F},
      title        = {{T}he late-onset {A}lzheimer’s disease risk factor
                      {RHBDF}2 is a modifier of microglial {TREM}2 proteolysis},
      journal      = {Life science alliance},
      volume       = {8},
      number       = {5},
      issn         = {2575-1077},
      address      = {Heidelberg},
      publisher    = {EMBO Press},
      reportid     = {DZNE-2025-00430},
      pages        = {e202403080},
      year         = {2025},
      abstract     = {The cell surface receptor TREM2 is a key genetic risk
                      factor and drug target in Alzheimer's disease (AD). In the
                      brain, TREM2 is expressed in microglia, where it undergoes
                      proteolytic cleavage, linked to AD risk, but the responsible
                      protease in microglia is still unknown. Another
                      microglial-expressed AD risk factor is catalytically
                      inactive rhomboid 2 (iRhom2, RHBDF2), which binds to and
                      acts as a non-catalytic subunit of the metalloprotease
                      ADAM17. A potential role in TREM2 proteolysis is not yet
                      known. Using microglial-like BV2 cells, bone marrow-derived
                      macrophages, and primary murine microglia, we identify
                      iRhom2 as a modifier of ADAM17-mediated TREM2 shedding. Loss
                      of iRhom2 increased TREM2 in cell lysates and at the cell
                      surface and enhanced TREM2 signaling and microglial
                      phagocytosis of the amyloid β-peptide (Aβ). This study
                      establishes ADAM17 as a physiological TREM2 protease in
                      microglia and suggests iRhom2 as a potential drug target for
                      modulating TREM2 proteolysis in AD.},
      keywords     = {Microglia: metabolism / Receptors, Immunologic: metabolism
                      / Receptors, Immunologic: genetics / Alzheimer Disease:
                      metabolism / Alzheimer Disease: genetics / Membrane
                      Glycoproteins: metabolism / Membrane Glycoproteins: genetics
                      / Animals / Proteolysis / Mice / ADAM17 Protein: metabolism
                      / Humans / Amyloid beta-Peptides: metabolism / Phagocytosis
                      / Macrophages: metabolism / Risk Factors / Carrier Proteins:
                      metabolism / Carrier Proteins: genetics / Signal
                      Transduction / Mice, Inbred C57BL},
      cin          = {AG Lichtenthaler / AG Tahirovic / AG Haass},
      ddc          = {570},
      cid          = {I:(DE-2719)1110006 / I:(DE-2719)1140003 /
                      I:(DE-2719)1110007},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC11909414},
      pubmed       = {pmid:40081988},
      doi          = {10.26508/lsa.202403080},
      url          = {https://pub.dzne.de/record/277534},
}